The pharmacokinetics of citrovorum factor (CF) are being studied in dogs and mice using 3H-D,L-CF and high pressure liquid chromatography to separate the metabolites. The biologically active (L) diasterioisomer of CF is measured by a biological assay. The pharmacokinetics of both isomers are being described and interactions with methotrexate are being studied. Alternatives to CF rescue of high dose MTX are being studied using thymidine, inosine and allopurinol (TIA). These studies are conducted in mice bearing L1210 tumor and TIA rescue is compared to CF rescue in an attempt to identify the mechanism of the increased therapeutic index achieved with high dose MTX followed by rescue.